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Exploiting zebrafish genetics to identify genes affecting addiction-related phenotypes.

Award Number: U01DA044400
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2018
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Exploiting zebrafish genetics to identify genes affecting addiction-related phenotypes. - Exploiting zebrafish genetics to identify genes affecting addiction-related phenotypes The cost of substance abuse in the US alone is estimated at $166 billion annually in preventable health care costs, with tobacco ($130 billion) and alcohol ($25 billion) abuse contributing to the overwhelming majority of this expense. The World Health Organization declared tobacco-related disease a global epidemic, predicted to cause an estimated 8 million annual deaths worldwide by 2030, if unabated. There is a vital need for increased understanding of the genetic and cell biological factors influencing vulnerability to addiction including smoking to help identify individuals at risk and to inform treatment strategies. As approaches to identify genetic risk are difficult in humans, research on genetic risk can be facilitated by the use of animal models. Zebrafish are an established developmental and behavioral genetic model species that show conserved responses to common drugs of abuse as well as behaviors that model core phenotypes predictive of vulnerability to addiction. We shall identify genes affecting core phenotypes associated with addiction by screening lines of ethyl nitrosurea (ENU)-mutagenised zebrafish for sensitivity to nicotine reward and impulsivity. We test the hypothesis that genes that show persistent adaptive changes in expression following chronic nicotine exposure are also addiction vulnerability genes. Our specific aims are: 1) To isolate 25 heritable loci affecting a) nicotine reward and b) impulsivity. i) We will use behavioral assays in adult ENU-mutagenized zebrafish to identify families showing altered nicotine reward and impulse control. We have developed a scalable, fully automated behavioral assay system for this purpose. We will use analysis of microarray or RNAseq data to identify genes that show persistent changes in expression following chronic nicotine exposure as candidates for genes affecting nicotine addiction vulnerability. We will pre-load the screen with families carrying mutations in these candidate genes. ii) We shall use exome sequencing to map the mutations in at least 10 families. The use of ENU- mutagenized lines facilitates identification of the causal mutations (by generation of strong phenotypes and/or by the ENU mutations acting as markers). 2) To identify the cell biological processes underlying the observed behavioral phenotypes. i) We shall use additional (predicted functional) ENU mutations or targeted knockouts of the identified genes to confirm genotype-phenotype associations. ii) We shall perform RNA sequencing to gain insight into possible effects on gene expression and cellular pathways affected. iii) We shall perform developmental analyses to test the hypothesis that behavioral effects are mediated by effects on neuronal patterning or neural circuit formation at developmental timepoints. The expected outcomes from this study are identification of novel genetic factors influencing core behaviors predictive of vulnerability to drug addiction and increased understanding of the cellular processes affected. These findings will enable future human genetic variation studies in these identified genes, with the potential to develop more personalized therapies. Results from this work will have a positive impact on individualized treatment efforts for tobacco dependence and addiction as a whole.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2022	QUEEN MARY UNIVERSITY OF LONDON	327 MILE END ROAD	LONDON				GBR	Drug Use and Addiction Research Programs	000	5	6/3/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	QUEEN MARY UNIVERSITY OF LONDON	327 MILE END ROAD	LONDON				GBR	Drug Use and Addiction Research Programs	000	5	4/5/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $419,015 )
2022	2022	QUEEN MARY UNIVERSITY OF LONDON	327 MILE END ROAD	LONDON				GBR	Drug Use and Addiction Research Programs	001	5	6/9/2022	NON-COMPETING CONTINUATION	$419,015
2022	2021	QUEEN MARY UNIVERSITY OF LONDON	327 MILE END ROAD	LONDON				GBR	Drug Use and Addiction Research Programs	000	4	5/10/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $419,015

Issue Date FY: 2021 ( Subtotal = $428,249 )
2021	2021	QUEEN MARY UNIVERSITY OF LONDON	327 MILE END ROAD	LONDON				GBR	Drug Use and Addiction Research Programs	000	4	8/2/2021	NON-COMPETING CONTINUATION	$428,249
														Subtotal = $428,249

Issue Date FY: 2020 ( Subtotal = $428,249 )
2020	2020	QUEEN MARY UNIVERSITY OF LONDON	327 MILE END ROAD	LONDON		E1 4NS		GBR	Drug Use and Addiction Research Programs	000	3	6/5/2020	NON-COMPETING CONTINUATION	$428,249
														Subtotal = $428,249

Issue Date FY: 2019 ( Subtotal = $428,249 )
2019	2019	QUEEN MARY UNIVERSITY OF LONDON	327 MILE END ROAD	LONDON		E1 4NS		GBR	Drug Use and Addiction Research Programs	001	2	5/15/2019	NON-COMPETING CONTINUATION	$428,249
2019	2018	QUEEN MARY UNIVERSITY OF LONDON	327 MILE END ROAD	LONDON		E1 4NS		GBR	Drug Use and Addiction Research Programs	000	1	5/14/2019	NEW	$0
														Subtotal = $428,249

Issue Date FY: 2018 ( Subtotal = $280,217 )
2018	2018	QUEEN MARY UNIVERSITY OF LONDON	327 MILE END ROAD	LONDON		E1 4NS		GBR	Drug Use and Addiction Research Programs	000	1	7/27/2018	NEW	$280,217
														Subtotal = $280,217

Grand Total All Awards = $1,983,979

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Exploiting zebrafish genetics to identify genes affecting addiction-related phenotypes.

Award Number: U01DA044400

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/01/2018

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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